This application relates to two other patent applications filed on an even date herewith: SAPPHYRINS, DERIVATIVES, AND SYNTHESES (by Sessler and Cyr Ser. No. 07/454,298) and PHOTODYNAMIC VIRAL DEACTIVATION WITH SAPPHYRINS (by Matthews, Sessler, Judy, Newman and Sogandares-Bernal Ser. No. 07/454,300).
The present invention relates to a photochemical method of producing singlet oxygen using sapphyrin compounds to generate a triplet excited state species which then interacts with molecular oxygen The resultant singlet oxygen is highly reactive and is potentially useful for a variety of medical applications. Discovery of the sapphyrin molecules as photosensitizers for singlet oxygen production appears likely to lead to efficient, localized, and selective in vivo therapy, especially in the emerging field of photodynamic tumor or viral therapy.
Investigations relating to the present invention were supported by Texas Advanced Research Program grant number 1581 and by the Biotechnology Resources Program of the NIH (RR 008866).
Macrocyclic ligands capable of complexing metal cations are finding an increasing number of applications in biomedical research, most specifically as photosensitizers in photodynamic therapy and as targets for magnetic resonance imaging processes. One approach to extending the range of compounds available for such studies involves the use of expanded porphyrins in which the basic ring structure is enlarged beyond the normal 18 .pi.-electrons periphery. Recently, the "texaphyrin" family of expanded porphyrins was introduced and shown to have useful photosensitizing properties ((a) Sessler, J. L.; Murai, T.; Lynch, V.; Cyr, M. J. Am. Chem. Soc. 1988, 110, 5586: (b) Sessler J. L.; Murai T.; Lynch, V. Inorg. Chem. 1989, 28, 1333: (c) Harriman, A.; Maiya, B. K.; Murai, T.; Hemmi, G.; Sessler, J. L.; Mallouk, T. E. J. Chem. Soc.. Chem. Commun. 1989, 314: (d) Maiya, B. K.; Harriman, A.; Sessler, J. L.; Hemmi, G.; Murai, T.; Mallouk, T. E. J. Phys. Chem. in press). This work is now extended to include "sapphyrin", a pentapyrrolic 22 .pi.-electron "expanded porphyrin" first prepared by the groups of Johnson and Woodward (Reported by R. B. Woodward at the Aromaticity Conference, Sheffield, U.K. 1966) a number of years ago but essentially unexplored in the years since ((a) Broadhurst, M. J.; Grigg, R. J. Chem. Soc., Perkin Trans. 1 1972, 2111; (b) Bauer, V. J; Clive, D. L. J.; Dolphin, D.; Paine III, J. B.; Harris, F. L.; King, M. M.; Lodger, J.; Wang, S.-W. C.; Woodward, R. B. J. Am. Chem. Soc. 1983, 105, 6429). The sapphyrins possess two properties which make them of potential interest for biomedical applications: First, they contain an unusually large central cavity which could provide an effective means of complexing large lanthanide cations for use in magnetic resonance imaging. Second, they absorb light strongly at a wavelength of about 680 nanometer (nm). The present invention relates to the synthesis of a sapphyrin molecule and investigation of its photophysical properties in various solvents. The most stable form of sapphyrin under such conditions is the diprotonated conjugate diacid (SAP.sup.2+) in which all five N-atoms are protonated and we have concentrated on this molecule, the structure of which is given in FIG. 1.
In a parallel study (Judy, M. M.; Mathews, J. L.; Boriak, R.; Skiles, H.; Cyr, M.; Maiya, B.G.; Sessler, J. L. Photochem. Photobiol. to be submitted), the present inventors have found that SAP.sup.2+ acts as an effective in vitro agent for the photodynamic inactivation (PDI) of herpes simplex virus (HSV). At a SAP.sup.2+ concentration of 60 .mu.M and with a light intensity of 10 J cm.sup.-2, a five logarithm killing of HSV is effected under conditions where little or no dark activity is detected. Singlet oxygen, directly or indirectly, appears to be the inactivating agent.
PDI-based purifications also appear to lend themselves to ex vivo photosensitized blood purification procedures. One method would be to generate matrix-supported PDI sapphyrin systems. A sapphyrin molecule would be attached to a solid matrix, such as polystyrene beads. Blood would then be irradiated, for example, while being passed through the sapphyrin-coated beads. Clearly, beads which do not absorb in the 680-730 nm range should be used since the sapphyrin compounds absorb in the 680-690 nm region. Carboxylated sapphyrins might be good candidates for attachment to amino-functionalized matrices. For example, sapphyrin 2 could be converted to an acid chloride after partial ester hydrolysis, then reacted with a pendant amino group (e.g., aminomethylated partially cross-linked Merrifield-type polystyrene) to form an amide linkage to the matrix.